Hyaluronic acid (HA) is a naturally occurring, high molecular weight polymer of repeating D-glucuronic .beta. (1-3) N-acetyl-D-glucosamine disaccharide subunits. The native forms are indeterminate in length. The structure of the molecule has been conserved throughout evolution, and is virtually identical between species. Due to its carbohydrate composition and ubiquitous distribution, most animals are immunologically tolerant of it
Several commercial uses of hyaluronic acid have been developed. These include using the natural water retention capacity of HA to maintain ocular fluid or to lubricate defective joints, employing the net-like structure of high molecular weight HA to capture drugs and carry them to the site of tissue damage, and blocking the metastases of HA binding tumor cells.
Hyaluronic acid is a ligand for a number of cell surface and extracellular matrix proteins, including ICAM-1 and CD44. Through these and other binding proteins, HA has been implicated in tumor metastasis, inflammation, cell division, wound healing, tissue hydration, and other biological functions.
Complex immune systems must achieve a delicate balance, where pathogens are recognized and eliminated, but host cells are safe from immune destruction. One mechanism for immune recognition is the expression of major histocompatibility complex proteins on the cell surface. These highly polymorphic proteins are a means of identifying cells as "self" or "foreign". During tissue transplantation, it is rare to find a perfect match between donor and host MHC antigens. The host immune system is therefore activated, and some level of immunosuppression is required to prevent graft rejection.
Immunosuppressants such as cyclosporin A, FK506, rapamycin and azathioprine have been used to prevent graft rejection, and to treat some forms of autoimmune disease. However, they have numerous side effects. There is therefore substantial interest in identifying new agents that can inhibit the activation of specific cells, particularly T cells, while having fewer side effects.
Relevant Literature
Bartolazzi et al. (1994) J. Exp. Med. 180:53-66 describes the interaction between CD44 and hyaluronate in the regulation of tumor development. The role of hyaluran-binding proteins in development, tissue homeostasis and disease is discussed in Knudsen and Knudsen (1993) FASEB J. 7:1233-1241.
Delfino et al. (1994) J Immunol 152:5171-9 discloses the role of CD44 in the development of natural killer cells from precursors in long-term cultures of mouse bone marrow. Lesley et al. (1994) J. Exp. Med. 180:383-387 finds that hyaluran binding function of CD44 is transiently activated on T cells during an in vivo immune response. The role of glycosaminoglycans in the regulation of T cell proliferation induced by thymic stroma-derived T cell growth factor is discussed in Kimura et al. (1991) J Immunol 146:2618-24. It is found that heparin and heparin sulfate inhibit T cell proliferation in the experimental system, but hyaluronic acid had no effect.
Galandrini et al. (1994) J Immunol 153:21-31 describes co-stimulation of human T cell effector functions with hyaluran. Funaro et al. (1994) Hum. Immunol. 40:267-78 discloses that stimulation of T cells via CD44 requires leukocyte-function-associated antigen interactions and interleukin-2 production.
Hyaluronic acid has been used as a carrier for drug delivery, described in U.S. Pat. No. 5,256,411 and International patent applications WO 91/04058 and WO 93/16733. Specific examples for ocular use are described in U.S. Pat. Nos. 4,839,342 and 5,411,952. U.S. Pat. No. 4,725,585 discloses the use of HA to normalize granulocytic phagocyte activity.